OA011-03. Clusterin, a natural ligand of DC-SIGN present in human semen inhibits HIV capture and transmission by dendritic cells

International audiencen.

TYMSTR, a putative chemokine receptor selectively expressed in activated T cells, exhibits HIV-1 coreceptor function

AbstractBackground: Chemokines bind to specific receptors and mediate leukocyte migration to sites of inflammation. Recently, some chemokine receptors, notably CXCR4 and CCR5, have been shown to be essential fusion factors on target cells for infection by human immunodeficiency virus (HIV); the chemokines bound by these receptors have also been shown to act as potent inhibitors of HIV infection. Here, we describe the isolation of a novel, putative chemokine receptor.Results: We have isolated the cDNA for a putative human chemokine receptor, which we have termed TYMSTR (T-lymphocyte-expressed seven-transmembrane domain receptor). The TYMSTR gene is localized to human chromosome 3 and encodes a protein that has a high level of identity with chemokine receptors. TYMSTR mRNA was selectively expressed in interleukin-2-stimulated T lymphocytes but not in freshly isolated lymphocytes and leukocytes or related cell lines. The natural ligand for TYMSTR was not identified among 32 human chemokines and other potential ligands. Cells co-expressing TYMSTR and human CD4 fused with cells expressing envelope glycoproteins of macrophage (M)-tropic HIV-1 as well as T-cell line (T)-tropic HIV-1 isolates. Addition of infectious, T-tropic HIV-1 particles to TYMSTR/CD4-expressing cells resulted in viral entry and proviral DNA formation.Conclusions: Our findings demonstrate that TYMSTR, in combination with CD4, mediates HIV-1 fusion and entry. The high-level expression of TYMSTR in CD4+ T lymphocytes and the selectivity of this receptor for T-tropic and M-tropic HIV-1 strains indicates that TYMSTR might function as HIV coreceptor at both early and late stages of infection

Compliance with current dietary recommendations and geographical variability of diet in women participating in 7 screening programs for breast cancer in Spain

Introducción: Una dieta saludable es especialmente importante durante la menopausia, periodo en el que aumenta el riesgo de varios problemas de salud. Analizamos la dieta de mujeres peri y postmenopáusicas españolas y el grado de cumplimiento de las recomendaciones actuales. Material y métodos: Estudio transversal en 3.574 mujeres de 45-68 años que acuden al cribado de cáncer de mama en 7 centros (A Coruña, Barcelona, Burgos, Palma de Mallorca, Pamplona, Valencia y Zaragoza). Se recogió la dieta mediante un cuestionario de frecuencia de alimentos validado para población española. Para la valoración del cumplimiento de las recomendaciones actuales se utilizaron los rangos recomendados por la Sociedad Española de Nutrición Comunitaria para ingesta de grupos de alimentos y las Ingestas Diarias Recomendadas (IDR) para energía, vitaminas y minerales de la Federación Española de Nutrición, Alimentación y Dietética. Resultados: El 29% de las mujeres eran obesas y un 42% tenía sobrepeso. El aporte calórico medio fue de 2.053 kcal (DE: 480). El perfil calórico general fue de: 43% de la energía aportada por lo carbohidratos, 36% por las grasas, 20% por las proteínas. Se evidenció una ingesta deficiente de vitamina D en todos los nodos del estudio, con una ingesta media general de 2,14 μg/día. Se detectó a su vez una ingesta deficitaria de vitamina E en A Coruña y Burgos. Todos los centros presentaron una ingesta elevada de productos lácteos y de legumbres. El consumo de frutas y verduras fue muy heterogéneo siendo especialmente elevada su ingesta en Mallorca y Valencia mientras que fue baja para ambos grupos de alimentos en A Coruña. La ingesta de aceite de oliva fue elevada en todos los centros exceptuando Burgos con un 74,3% de las mujeres estudiadas por debajo de las 3 raciones al día recomendadas. Conclusiones: Una dieta con menos grasas y proteínas y más rica en vegetales, frutos secos y alimentos ricos en hidratos de carbono equilibraría el balance energético y mejoraría la calidad de la dieta corrigiendo las bajas ingestas de vitaminas D y E. Estas recomendaciones son especialmente importantes en las ciudades más alejadas de la costa mediterránea donde se han detectado mayores incumplimientos de las recomendaciones vigentes y una dieta más alejada de la dieta mediterránea.Introduction: A healthy diet is especially important during menopause, a period which increases the risk of various health problems. We analyzed the diet of periand postmenopausal Spanish women and the degree of compliance with current recommendations. Material and methods: We studied 3574 women 45-68 years old who attended breast cancer screening programmes in 7 centres (A Coruña, Barcelona, Burgos, Palma de Mallorca, Pamplona, Valencia and Zaragoza). Diet information was collected using a food frequency questionnaire validated for the Spanish population. For the assessment of compliance with current guidelines we used the recommendations by the Spanish Society of Community Nutrition for food groups intake and by the Spanish Federation of Nutrition, Food and Dietetics for energy, vitamins and minerals intake. Results: The 29% of women were obese and 42% overweight. The average caloric intake was 2.053 kcal (SD 480). The general energy profile was: 43% of the energy from the carbohydrates, 36% from fats, and 20% from proteins. There was a low vitamin D intake in all centres of the study, with an overall mean intake of 2.14 mg/day. A deficit of vitamin E intake in A Coruña and Burgos was also detected. Intake of dairy products and vegetables was high in all the study centers. The consumption of fruits and vegetables was very heterogeneous, with high intakes observed in Mallorca and Valencia and low for both food groups in A Coruña. The olive oil intake was high in all centers except Burgos with 74.3% of the women studied below the recommended 3 servings per day. Conclusions: A diet with less fat and protein and a higher consumption of vegetables, nuts and foods rich in carbohydrate might balance the energy intake and improve the quality of the diet correcting the low intakes of vitamins D and E. These recommendations are especially important in cities far from the Mediterranean coast where more breaches have been detected over the current recommendations with a lower adherence to the Mediterranean diet.Este estudio ha recibido financiación del Fondo de Investigación Sanitaria (proyecto PI060386) y de Astra-Zéneca (convenio de colaboración entre Astra- Zeneca y el Instituto de salud Carlos III 1306-1306 EPY

CCR5 Haplotypes and Mother-to-Child HIV Transmission in Malawi

CCR5 and CCR2 gene polymorphisms (SNPs) have been associated with protection against HIV transmission in adults and with delayed progression to AIDS. The CCR5 Delta32 deletion and SNP -2459G are associated with reduced expression of the CCR5 protein.We investigated the association between infant CCR2/CCR5 diplotype and HIV mother to child transmission (MTCT) in Malawi. Blood samples from infants (n = 552) of HIV positive women who received nevirapine were genotyped using a post-PCR multiplex ligase detection reaction and haplotypes were identified based on 8 CCR2/CCR5 SNPs and the open reading frame 32 base pair deletion. Following verification of Hardy-Weinberg equilibrium, log linear regression was performed to examine the association between mutations and MTCT. Overall, protection against MTCT was weakly associated with two CCR5 SNPs, -2459G (Risk ratio [RR], 0.78; confidence interval [CI], 0.54-1.12), and the linked CCR5 -2135T (RR, 0.78; CI, 0.54-1.13). No child carried the CCR5 Delta32 SNP. Maternal Viral Load (MVL) was found to be an effect measure modifier. Among mothers with low MVL, statistically significant protection against MTCT was observed for -2459G (RR, 0.50; CI, 0.27-0.91), and -2135T (RR, 0.51; CI, 0.28-0.92). Statistically significant protection was not found at high MVL.Results from this study suggest that CCR5 SNPs -2459G and -2135T associated with reduced receptor expression protect against MTCT of HIV at low MVLs, whereas high MVLs may over-ride differences in coreceptor availability

ISG15 Is Critical in the Control of Chikungunya Virus Infection Independent of UbE1L Mediated Conjugation

Chikungunya virus (CHIKV) is a re-emerging alphavirus that has caused significant disease in the Indian Ocean region since 2005. During this outbreak, in addition to fever, rash and arthritis, severe cases of CHIKV infection have been observed in infants. Challenging the notion that the innate immune response in infants is immature or defective, we demonstrate that both human infants and neonatal mice generate a robust type I interferon (IFN) response during CHIKV infection that contributes to, but is insufficient for, the complete control of infection. To characterize the mechanism by which type I IFNs control CHIKV infection, we evaluated the role of ISG15 and defined it as a central player in the host response, as neonatal mice lacking ISG15 were profoundly susceptible to CHIKV infection. Surprisingly, UbE1L−/− mice, which lack the ISG15 E1 enzyme and therefore are unable to form ISG15 conjugates, displayed no increase in lethality following CHIKV infection, thus pointing to a non-classical role for ISG15. No differences in viral loads were observed between wild-type (WT) and ISG15−/− mice, however, a dramatic increase in proinflammatory cytokines and chemokines was observed in ISG15−/− mice, suggesting that the innate immune response to CHIKV contributes to their lethality. This study provides new insight into the control of CHIKV infection, and establishes a new model for how ISG15 functions as an immunomodulatory molecule in the blunting of potentially pathologic levels of innate effector molecules during the host response to viral infection

Compliance with current dietary recommendations and geographical variability of diet in women participating in 7 screening programs for breast cancer in Spain.

[ES] Introducción:Una dieta saludable es especialmenteimportante durante la menopausia, periodo en el queaumenta el riesgo de varios problemas de salud. Analiza-mos la dieta de mujeres peri y postmenopáusicas españo-las y el grado de cumplimiento de las recomendacionesactuales. Material y métodos:Estudio transversal en 3.574 muje-res de 45-68 años que acuden al cribado de cáncer demama en 7 centros (A Coruña, Barcelona, Burgos, Palmade Mallorca, Pamplona, Valencia y Zaragoza). Se recogióla dieta mediante un cuestionario de frecuencia de ali-mentos validado para población española. Para la valora-ción del cumplimiento de las recomendaciones actuales seutilizaron los rangos recomendados por la SociedadEspañola de Nutrición Comunitaria para ingesta de gru-pos de alimentos y las Ingestas Diarias Recomendadas(IDR) para energía, vitaminas y minerales de la Federa-ción Española de Nutrición, Alimentación y Dietética. Resultados:El 29% de las mujeres eran obesas y un42% tenía sobrepeso. El aporte calórico medio fue de2.053 kcal (DE: 480). El perfil calórico general fue de: 43% de la energía aportada por lo carbohidratos, 36%por las grasas, 20% por las proteínas. Se evidenció unaingesta deficiente de vitamina D en todos los nodos delestudio, con una ingesta media general de 2,14 μg/día. Sedetectó a su vez una ingesta deficitaria de vitamina E en ACoruña y Burgos. Todos los centros presentaron unaingesta elevada de productos lácteos y de legumbres. Elconsumo de frutas y verduras fue muy heterogéneosiendo especialmente elevada su ingesta en Mallorca yValencia mientras que fue baja para ambos grupos de ali-mentos en A Coruña. La ingesta de aceite de oliva fue ele-vada en todos los centros exceptuando Burgos con un74,3% de las mujeres estudiadas por debajo de las 3raciones al día recomendadas. Conclusiones:Una dieta con menos grasas y proteínasy más rica en vegetales, frutos secos y alimentos ricos enhidratos de carbono equilibraría el balance energético ymejoraría la calidad de la dieta corrigiendo las bajasingestas de vitaminas D y E. Estas recomendaciones sonespecialmente importantes en las ciudades más alejadasde la costa mediterránea donde se han detectado mayoresincumplimientos de las recomendaciones vigentes y unadieta más alejada de la dieta mediterránea. [EN] A healthy diet is especially important during menopause, a period which increases the risk of various health problems. We analyzed the diet of periand postmenopausal Spanish women and the degree of compliance with current recommendations. We studied 3574 women 45-68 years old who attended breast cancer screening programmes in 7 centres (A Coruña, Barcelona, Burgos, Palma de Mallorca, Pamplona, Valencia and Zaragoza). Diet information was collected using a food frequency questionnaire validated for the Spanish population. For the assessment of compliance with current guidelines we used the recommendations by the Spanish Society of Community Nutrition for food groups intake and by the Spanish Federation of Nutrition, Food and Dietetics for energy, vitamins and minerals intake. The 29% of women were obese and 42% overweight. The average caloric intake was 2.053 kcal (SD 480). The general energy profile was: 43% of the energy from the carbohydrates, 36% from fats, and 20% from proteins. There was a low vitamin D intake in all centres of the study, with an overall mean intake of 2.14 mg/day. A deficit of vitamin E intake in A Coruña and Burgos was also detected. Intake of dairy products and vegetables was high in all the study centers. The consumption of fruits and vegetables was very heterogeneous, with high intakes observed in Mallorca and Valencia and low for both food groups in A Coruña. The olive oil intake was high in all centers except Burgos with 74.3% of the women studied below the recommended 3 servings per day. A diet with less fat and protein and a higher consumption of vegetables, nuts and foods rich in carbohydrate might balance the energy intake and improve the quality of the diet correcting the low intakes of vitamins D and E. These recommendations are especially important in cities far from the Mediterranean coast where more breaches have been detected over the current recommendations with a lower adherence to the Mediterranean diet.Este estudio ha recibido financiación del Fondo deInvestigación Ssanitaria (proyecto PI060386) y de Astra-Zéneca (convenio de colaboración entre Astra-Zeneca y el Instituto de salud Carlos III 1306-1306EPY).S

Menstrual and Reproductive Factors and Risk of Gastric and Colorectal Cancer in Spain

BACKGROUND: Sex hormones play a role in gastric cancer and colorectal cancer etiology, however, epidemiological evidence is inconsistent. This study examines the influence of menstrual and reproductive factors over the risk of both tumors. METHODS: In this case-control study 128 women with gastric cancer and 1293 controls, as well as 562 female and colorectal cancer cases and 1605 controls were recruited in 9 and 11 Spanish provinces, respectively. Population controls were frequency matched to cases by age and province. Demographic and reproductive data were directly surveyed by trained staff. The association with gastric, colon and rectal cancer was assessed using logistic and multinomial mixed regression models. RESULTS: Our results show an inverse association of age at first birth with gastric cancer risk (five-year trend: OR = 0.69; p-value = 0.006). Ever users of hormonal contraception presented a decreased risk of gastric (OR = 0.42; 95%CI = 0.26-0.69), colon (OR = 0.64; 95%CI = 0.48-0.86) and rectal cancer (OR = 0.61; 95%CI = 0.43-0.88). Postmenopausal women who used hormone replacement therapy showed a decreased risk of colon and rectal tumors. A significant interaction of educational level with parity and months of first child lactation was also observed. CONCLUSION: These findings suggest a protective role of exogenous hormones in gastric and colorectal cancer risk. The role of endogenous hormones remains unclear

CXCL12 expression by healthy and malignant ovarian epithelial cells

<p>Abstract</p> <p>Background</p> <p>CXCL12 has been widely reported to play a biologically relevant role in tumor growth and spread. In epithelial ovarian cancer (EOC), CXCL12 enhances tumor angiogenesis and contributes to the immunosuppressive network. However, its prognostic significance remains unclear. We thus compared CXCL12 status in healthy and malignant ovaries, to assess its prognostic value.</p> <p>Methods</p> <p>Immunohistochemistry was used to analyze CXCL12 expression in the reproductive tracts, including the ovaries and fallopian tubes, of healthy women, in benign and borderline epithelial tumors, and in a series of 183 tumor specimens from patients with advanced primary EOC enrolled in a multicenter prospective clinical trial of paclitaxel/carboplatin/gemcitabine-based chemotherapy (GINECO study). Univariate COX model analysis was performed to assess the prognostic value of clinical and biological variables. Kaplan-Meier methods were used to generate progression-free and overall survival curves.</p> <p>Results</p> <p>Epithelial cells from the surface of the ovary and the fallopian tubes stained positive for CXCL12, whereas the follicles within the ovary did not. Epithelial cells in benign, borderline and malignant tumors also expressed CXCL12. In EOC specimens, CXCL12 immunoreactivity was observed mostly in epithelial tumor cells. The intensity of the signal obtained ranged from strong in 86 cases (47%) to absent in 18 cases (<10%). This uneven distribution of CXCL12 did not reflect the morphological heterogeneity of EOC. CXCL12 expression levels were not correlated with any of the clinical parameters currently used to determine EOC prognosis or with HER2 status. They also had no impact on progression-free or overall survival.</p> <p>Conclusion</p> <p>Our findings highlight the previously unappreciated constitutive expression of CXCL12 on healthy epithelia of the ovary surface and fallopian tubes, indicating that EOC may originate from either of these epithelia. We reveal that CXCL12 production by malignant epithelial cells precedes tumorigenesis and we confirm in a large cohort of patients with advanced EOC that CXCL12 expression level in EOC is not a valuable prognostic factor in itself.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov: <a href="http://www.clinicaltrials.gov/ct2/show/NCT00052468">NCT00052468</a></p

Games of Incomplete Information and Myopic Equilibria

A new concept of an equilibrium in games is introduced that solves an open question posed by A. Neyman

Intracellular expression of Tat alters mitochondrial functions in T cells: a potential mechanism to understand mitochondrial damage during HIV-1 replication

HIV-1 replication results in mitochondrial damage that is enhanced during antiretroviral therapy (ART). The onset of HIV-1 replication is regulated by viral protein Tat, a 101-residue protein codified by two exons that elongates viral transcripts. Although the first exon of Tat (aa 1–72) forms itself an active protein, the presence of the second exon (aa 73–101) results in a more competent transcriptional protein with additional functions. Results: Mitochondrial overall functions were analyzed in Jurkat cells stably expressing full-length Tat (Tat101) or one-exon Tat (Tat72). Representative results were confirmed in PBLs transiently expressing Tat101 and in HIV-infected Jurkat cells. The intracellular expression of Tat101 induced the deregulation of metabolism and cytoskeletal proteins which remodeled the function and distribution of mitochondria. Tat101 reduced the transcription of the mtDNA, resulting in low ATP production. The total amount of mitochondria increased likely to counteract their functional impairment. These effects were enhanced when Tat second exon was expressed. Conclusions: Intracellular Tat altered mtDNA transcription, mitochondrial content and distribution in CD4+ T cells. The importance of Tat second exon in non-transcriptional functions was confirmed. Tat101 may be responsible for mitochondrial dysfunctions found in HIV-1 infected patients.We greatly appreciate the secretarial assistance of Mrs Olga Palao. This work was supported by FIPSE (360924/10), Spanish Ministry of Economy and Competitiveness (SAF2010-18388), Spanish Ministry of Health (EC11- 285), AIDS Network ISCIII-RETIC (RD12/0017/0015), Instituto de Salud Carlos III, Spanish Ministry of Economy and Competitiveness (FIS PI12/00506). The work of Sara Rodríguez-Mora is supported by a fellowship of Sara Borrell from Spanish Ministry of Economy and Competitiveness (2013). The work of María Rosa López-Huertas is supported by a fellowship of the European Union Programme Health 2009 (CHAARM).S